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Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children’s evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients. In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.

Simple Summary Tumor suppressor genes are critical in the control of many biological functions. They can be classified based on their roles in proliferation, cell-cycle progression, DNA repair/damage, and crucial signaling functions, including apoptosis, autophagy, and necrosis. The absence of functional tumor suppressor genes entails a higher risk of dysfunction of cell growth, differentiation, cell death, and cancer development. Loss of function or mutations of such genes has been identified in many types of cancer, such as breast, bladder, colorectal, head and neck, lung, ovarian, uterine, and pancreatic cancers. Familial cancer syndromes, such as Li–Fraumeni syndrome, are associated with loss of TP53 function. Extensive studies have been carried out to clarify the roles of the products of these genes, as well as their mechanistic link to cancers, to identify novel targets for specific cancer types. Here, we introduce the roles of tumor suppressor gene products in pancreatic cancer development and its therapeutics for tumorigenesis prevention. Abstract The high mortality of pancreatic cancer is attributed to the insidious progression of this disease, which results in a delayed diagnosis and advanced disease stage at diagnosis. More than 35% of patients with pancreatic cancer are in stage III, whereas 50% are in stage IV at diagnosis. Thus, understanding the aggressive features of pancreatic cancer will contribute to the resolution of problems, such as its early recurrence, metastasis, and resistance to chemotherapy and radiotherapy. Therefore, new therapeutic strategies targeting tumor suppressor gene products may help prevent the progression of pancreatic cancer. In this review, we discuss several recent clinical trials of pancreatic cancer and recent studies reporting safe and effective treatment modalities for patients with advanced pancreatic cancer.

Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers.

Background: CD19 targeting chimeric antigen receptor (CAR) T cells have induced unprecedented remission rates in high-risk precursor B Acute Lymphoblastic Leukemia (ALL); however recurrent disease with CD19 antigen escape variants is not uncommon. Therefore, we developed a novel CD22 targeting CAR, and following preclinical validation, tested it in a first-in-human pediatric and young adult phase 1 clinical trial, PLAT-04 (NCT03244306). Four subjects were treated at 2 dose levels (DL) (1x10 6/kg (DL1) and 3x10 6/kg (DL2)). The CD22 CAR T cell product (SCRI-CAR22v1) was successfully manufactured (n=4) and no dose limiting toxicity (DLTs), cytokine release syndrome (CRS) or neurotoxicity was observed. However, all subjects had minimal CAR T cell expansion, with 3 of 4 subjects demonstrating persistent or progressive disease at day 21 evaluation despite continued CD22 expression on leukemic blasts. Based on the poor in vivo expansion and lack of activity, enrollment was voluntarily halted to interrogate and optimize the CAR construct for enhanced performance. Methods: Human T cells were transduced to express one of two CD22 CAR constructs. We designed SCRI-CAR22v2, a CD22 CAR that utilizes the same scFv as SCRI-CAR22v1 but with a shorter linker between M971 VH and VL and a shorter hinge with differing transmembrane region, and both using CD8 alpha (Figure A). This construct maintained the truncated EGFR extracellular tag (EGFRt) for tracking and potential in vivo suicide mechanism. The two transduced CAR T cell products were compared preclinically by flow cytometry, chromium release assay and in an in vivo murine model to understand differing T cell activity between the CAR constructs. Additionally, SCRI-CAR22v2 is currently under investigation in a dose finding phase 1 clinical trial, PLAT-07 (NCT04571138). Results: Following use of cetuximab-APC and biotinylated anti-human Fab antibody for surface EGFRt and CAR detection, the SCRI-CAR22v1 expresses lower levels of EGFRt but similar CAR levels on the cell surface demonstrated by MFI (Figure B). Biotinylated, soluble CD22 antigen was also used to evaluate CD22 CAR receptor activity and, as measured by MFI, a higher affinity is suggested via SCRI-CAR22v2 as compared to SCRI-CAR22v1 (Figure B). K562 cells expressing low, medium or high CD22 were used to evaluate the impact of surface antigen expression on the CAR activity level. SCRI-CAR22v2 demonstrates improved targeted cell lysis at all 3 antigen quantity levels by chromium release assay (Figure C). In NSG mice inoculated with Raji tumor cells expressing ffluc, SCRI-CAR22v2 demonstrated improved survival compared to SCRI-CAR22v1 (Figure D) and clearance of Raji tumor cells (Figure E). Based on this promising preclinical data, we initiated enrollment onto PLAT-07, a phase 1 dose finding trial (2x10 5cells/kg (DL1), 5x10 5cells/kg (DL2) and 1x10 6cells/kg (DL3)) of SCRI-CAR22v2. To date, 3 subjects have been enrolled and successfully infused at DL1. All had prior CD19-CAR therapy and 2 lacked CD19 leukemic expression at the time of SCRI-CAR22v2 infusion. At the time of cell infusion, one subject had only extramedullary disease, one had MRD of Conclusions: Despite encouraging preclinical data, SCRI-CAR22v1 demonstrated poor expansion and engraftment in a Phase 1 trial. Notably, minor CAR alterations lead to encouraging in-human activity in early clinical findings. Our experience suggests a shorter linker and hinge as well as incorporation of an CD8 alpha transmembrane region improves the clinical activity of CD22 targeted CAR T cells in subjects with recurrent disease following CD19 CAR T cells. Further evaluation is needed to elucidate the critical CAR components and/or assays at the preclinical level that can best predict which CAR should be brought to the clinic for further evaluation. Figure 1 Figure 1. Disclosures Orentas: Lentigen: Patents & Royalties. Jensen: BMS: Patents & Royalties; Umoja Biopharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Research Funding. Gardner: Novartis: Consultancy; BMS: Patents & Royalties.

Following preclinical optimization of B7-H3-specific CAR T cells against pediatric brain tumor models, we opened BrainChild-03 (NCT04185038), a phase 1 clinical trial of repeatedly dosed, outpatient, locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or diffuse intrinsic pontine glioma (DIPG). Here, we report the interim findings from patients enrolled on Arm C, dedicated to DIPG. The primary endpoints are feasibility and safety, with secondary endpoints of disease response. We utilize second-generation CAR T cells with a 4-1BB costimulatory domain and a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S), allowing for methotrexate selection. We do not deliver conditioning chemotherapy. The first three evaluable patients with DIPG all met feasibility for generating a balanced CD4:CD8 CAR T cell product, with 3.85x109 CAR T cells generated for S005, 4.29x109 for S008, and 2.45x109 for S012, allowing for greater than 6 months of biweekly dosing for each patient. All subjects were treated at Dose Level 1 (1x107 CAR T cells). S005 received 10 doses before clinical progression greater than 2 years from diagnosis, S008 has received 10 doses and continues on therapy with decreased tumor volume, and S012 has received 5 doses and continues on study with stable disease. There have been no dose limiting toxicities (DLT). 3/3 patients exhibited post infusion fever, headache, and elevated serum CRP but no evidence of cytokine release syndrome (CRS) or systemic CAR T cells. 0/3 patients required PICU admissions. In the cerebrospinal fluid (CSF), 2/3 patients have had elevations of cytokines such as CXCL10 and CCL2, as well as circulating CSF CAR T cells. Advanced serial patient CSF proteomic and transcriptomic profiling are underway. Ultimately, this report provides preliminary evidence that outpatient locoregional B7-H3 CAR T cells for children with DIPG may be feasible and tolerable.

Introduction Axillary lymph node dissection is standard therapy for patients with positive-node breast cancer, and can be performed with an electrocautery scalpel and suture ligation in most cases. However, knot slipping can occur during suture ligation and this can spread thermal damage to peripheral tissues. The LigaSureTM Small Jaw vessel-sealing system was developed as an alternative to suture ligatures, staplers, and other energy-dependent devices for sealing blood and lymphatic vessels, but its use in axillary dissection for breast cancer is limited. We prospectively compared the duration until drain removal after surgery, total lymph fluid drainage volume, intraoperative blood loss, and incidence of complications after axillary dissections, between this device and conventional methods. Methods This prospective randomized study was conducted at the Department of Breast and Endocrine Surgery at Tokai University School of Medicine, Kanagawa, Japan, between October 2011 and March 2015. Major eligibility criteria included (1) pathologically confirmed breast cancer diagnosis, (2) age ≥20 and ≤80 years, and (3) a signed informed consent form. The primary endpoint was duration until drain removal after surgery. The secondary endpoints were total lymph fluid drainage volume, intraoperative blood loss, and incidence of postoperative surgical complications. We defined the criterion for drain removal as a lymph fluid drainage volume of Results Initially, 100 patients were assigned as eligible; however, two patients were later excluded because of the exclusion criteria. Of 98 patients, 49 were randomized to the study group, and 49 to the control group. The mean duration until drain removal after surgery was 5.2 days in the study group and 5.0 days in the control group (p=0.573). The mean total lymph fluid drainage volumes were 260.3 and 233.5 mL (p=0.502), and the mean intraoperative blood loss volumes were 17.8 and 18.0 mL (p=0.949), for the study and control groups, respectively. No significant differences were found between the two groups regarding drain removal duration, total drainage volume, and intraoperative blood loss volume. Both groups had low incidence rates of postoperative hematoma, wound infection, lymphedema, and pain, and had similar incidence rates of seroma formation after drain removal. Conclusion Our study results indicated that the use of the LigaSureTM Small Jaw in axillary dissection for breast cancer was as safe as conventional methods. However, using the LigaSureTM Small Jaw did not improve surgical outcomes such as duration until drain removal and total lymph fluid drainage volume compared with conventional methods. Citation Format: Okamura T, Niikura N, Yokoyama K, Ogiya R, Oshitanai R, Terao M, Morioka T, Tsuda B, Saito Y, Suzuki Y, Tokuda Y. Utility of LigaSureTM vessel-sealing device in axillary dissection for breast cancer surgery: A randomized single center study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-11.

We have applied the photoexcited muon spin spectroscopy technique (photo-$\mu$SR) to intrinsic germanium with the goal of developing a new method for characterizing excess carrier kinetics in a wide range of semiconductors. Muon spin relaxation rates can be a unique measure of excess carrier density and utilized to investigate carrier dynamics. The obtained carrier lifetime spectrum can be modeled with a simple diffusion equation to determine bulk recombination lifetime and carrier mobility. Temperature dependent studies of these parameters can reveal the recombination and diffusion mechanism., Comment: 4 pages, 3 figures

Muons, as a bulk probe of materials, have been used to study the depth profile of charge carrier kinetics in Si wafers by scanning the muon implantation depth. The photoexcited muon spin spectroscopy technique can optically generate excess carriers in semiconductor wafers, while muons can measure the excess carrier density. As a result, carrier recombination lifetime spectra can be obtained. The depth-dependent lifetime spectra enable us to accurately measure the bulk carrier lifetime and surface recombination velocity by fitting the spectra to a simple 1-dimensional diffusion model. Unlike other traditional lifetime spectroscopy techniques, the bulk and surface recombination properties can be readily de-convoluted in this method. Here, we have applied the technique to study silicon wafers both with and without passivation treatment, and have demonstrated that the model can correctly describe the carrier kinetics in these two cases., Comment: 5 pages, 2 figures

Background Few reports of the real-world efficacy and safety of tofacitinib (TFB) in Asians are available, and potential predictors of the response to therapy are unclear. We investigated the efficacy and safety profiles of TFB treatment for one year in patients with active Ulcerative Colitis (UC) in our specialized Inflammatory Bowel Disease center. Methods This study included 111 patients who received TFB between May 2018 and February 2020. We assessed disease activity using the partial Mayo Score (pMS). Clinical remission was defined as pMS ≤2, with no subscore >1 and a rectal bleeding subscore of 0. Clinical response was defined as a decrease in pMS of ≥2 points from baseline with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of ≤1 point. Results Mean patient age was 35 years (interquartile range [IQR]: 28-47), 60 (59.4%) were men, and mean disease duration was 4.8 years (IQR:1.5-10). The pMS was 6 (IQR:4-7) and C-reactive protein was 0.30 mg/dl (IQR: 0.1-1.0). At baseline, 63 (62.4%) patients received an anti-TNFα agent, 11 (10.9%) received vedolizumab, and 7 (6.9%) received both. Clinical response and clinical remission were, respectively, 66.3% (67/101) and 50.5% (51/101) at week 8, and 47.1% (40/85) and 43.5% (37/85) at week 48. The cumulative remission rate was 61.7% at 1 year and 51.7% at 2 years, and tended to be better in the ≥2 anti-TNFα agents failure group than in the 1 anti-TNFα agent failure and bio-naïve groups (P=0.10). Cumulative colectomy-free survival was 91.9% at 1 year and 89.1% at 2 years. Cumulative drug-free survival in the non-remission group at week 8 was 30.9% at 1 year and 30.9% at 2 years, significantly lower than in the remission-achieving group at week 8 (P Conclusion TFB was more effective in low-activity UC patients and its efficacy was not affected by previous treatment with anti-TNF agents. Most patients in the remission groups at week 8 could continue TFB for one year without severe adverse events, although careful monitoring for herpes zoster is necessary. The risk of thrombotic adverse events might be lower in Japanese UC patients.

To identify proteins related to the pathophysiology of aortic valve stenosis (AS), we investigated the protein profiles of AS aortic valves. Specifically, proteins were extracted from a thickened and calcified area (AS-C) and an apparently non-thickened and non-calcified area (AS-N) in an identical aortic valve leaflet in each of 6 AS patients. The proteins were then separated by 2-dimensional gel electrophoresis (2DE). Protein spots detected by 2DE were compared between the AS-C and AS-N samples. Protein spots of interest were subjected to protein identification by mass spectrometry.In total, 670 protein spots were detected by 2DE, 28 of which showed more than 1.5-fold different intensity (P < 0.05) between the AS-C and AS-N samples. Proteins were identified in 17 out of the 28 spots. Fibrinogen and lumican were identified in 9 and 3 spots, respectively. Intensity of these 12 spots was lower in the AS-C samples than in the AS-N samples. In the 1D-Western blot analysis, 4 lumican bands (80 kDa, 75 kDa, 65 kDa, and 53 kDa) were detected, of which 2 bands with 80 kDa and 75 kDa showed lower intensity in the AS-C samples than in the AS-N samples. When de-glycosylated protein samples were used in the 1D-Western blot, only a single lumican band with ~40 kDa was detected, indicating that lumican was variously glycosylated and that highly glycosylated lumican molecules were decreased in AS-C.Collectively, insufficient glycosylation of lumican in the thickened and calcified areas of AS aortic valves may be involved in the pathophysiology of AS.

Background Immune checkpoint therapy only benefits a fraction of patients, thus huge efforts have been made to develop predictive biomarkers to identify those patients. Immune biomarkers like PD-L1 expression are extremely dynamic and the timing of evaluation, on primary or metastatic disease, may be critical. We have already shown that tumour-infiltrating lymphocytes (TILs) decrease during metastatic progression in triple-negative (TN) and human epidermal growth factor-2 positive (HER2+) breast cancers (Ogiya R, ASCO 2015), suggesting that mechanisms of immune escape contribute and favour the metastatic progression. In this work we aimed to characterize the modulation and changes of specific immune markers during the metastatic spread comparing paired samples from primary and recurrent breast cancers. Methods We retrospectively identified 25 patients with HER2+ (n = 14) and TN (n = 11) early breast cancer diagnosed between 1990 and 2009 at Tokai University Hospital, and who subsequently experienced a first regional or distant recurrence confirmed by tumour biopsy/resection. Haematoxylin and eosin-stained slides of these paired samples were evaluated for stromal TILs. Immunohistochemical staining was performed using primary antibodies against CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA-class I. Results The sites of first recurrence was the skin (n = 7), brain (n = 6), lymph node (n = 4), lung (n = 3), bone (n = 2), and one of each of bone marrow, liver and muscle. Immunohistochemical evaluations could not be performed in 5 primary tumours and 2 recurrent tumours because of the small quantity of the specimens. The percentage of CD8+ T cells staining in the primary tumours was significantly higher (median 16%) than that in recurrent tumours (median 10%) (paired t-test, p = 0.008) Similarly, the percentage of CD4+ T cells staining in the primary tumours was significantly higher (median 40%) than that in recurrent tumours (median 25%) (p = 0.026). The percentage of Foxp3+ T cells was low ( Comparison of positivity rate between primary and recurrent tumours for each antibody Primary tumourRecurrent tumourPTotal breast tumours (N)2023 TILs positivity rate, median (%) CD440%25%.03CD816%10%.01Foxp3 Conclusions Tumours at first metastatic recurrence in HER2+ and TN breast cancers have a lower percentage of both CD8+ and CD4+ T cells compared to primary tumours, confirming a potential role of immune escape in tumour progression. Other immune markers, including PD-L1, were not found to change significantly, but negative/positive conversions were observed. This suggest that an evaluation of disease at the time of immunotherapy administration might be more informative. These findings warrant larger confirmation studies. Citation Format: Ogiya R, Niikura N, Kumaki N, Bianchini G, Kitano S, Iwamoto T, Hayashi N, Yokoyama K, Oshitanai R, Terao M, Morioka T, Tsuda B, Okamura T, Saito Y, Suzuki Y, Tokuda Y. Difference of immune microenvironment between primary and recurrent tumours in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-13.

Luxtera and TSMC have jointly developed a new generation 100Gbps/λ-capable silicon photonics platform in a commercial 300 mm CMOS line. We present process details and the performance of the photonic device library.

The c-Jun Dimerization Protein 2, JDP2, is a basic leucine zipper protein member of the activator protein-1 (AP-1) family of transcription factors. JDP2 typically suppresses gene transcription through multiple mechanisms and plays a dual role in multiple cellular processes, including cell differentiation and proliferation which is dependent on AP-1 function. Whereas the role of JDP2 expression within cancer cells has been studied, its role in stromal cells at the tumor microenvironment is largely unknown. Here we show that mice lacking JDP2 (JDP2-/-) display a reduced rate of metastasis in Lewis lung carcinoma (LLC) and polyoma middle T-antigen (PyMT) breast carcinoma mouse models. The replacement of wild-type bone marrow derived cells (BMDCs) with JDP2-deficient BMDCs recapitulates the metastatic phenotype of JDP2-/- tumor-bearing mice. In vitro, conditioned medium of wild-type BMDCs significantly potentiates the migration and invasion capacity of LLC cells as compared to that of JDP2-/- BMDCs. Furthermore, wild-type BMDCs secrete CCL5, a chemokine known to contribute to metastasis, to a greater extent than JDP2-/- BMDCs. The supplementation of CCL5 in JDP2-/- BMDC conditioned medium was sufficient to potentiate the invasion capacity of LLC. Overall, this study suggests that JDP2-expressing BMDCs within the tumor microenvironment contribute to metastatic spread.

In order to stay in good health, people have regular checkups. Part of this process involves examining the body for abnormalities. This requires a variety of large, complicated medical equipment to measure a small amount of biomolecules or chemical substances. The rapid advances in microelectromechanical systems (MEMS) and nanotechnology have made it possible to downsize medical equipment and perform health checkups using simpler detection methods such as label-free measurements. Nanomaterials have been used to achieve these goals; however, these require high-level sensor fabrication techniques and may provide lower sensitivity than conventional methods. In this work, we developed a compact label-free small molecule measurement system using a periodically nanostructured sensor substrate. We fabricated the sensor substrate using simple techniques, namely, thermal nanoimprinting and sputtering. The sensor substrate realizes label-free measurements by utilizing surface plasmon resonance (SPR). A collimator is mounted into an optical fiber to reduce noise in real-time measurements. The flow cell height and velocity were investigated with the aim of shortening the equilibrium binding time. We demonstrate the simple yet effective method by performing label-free measurement of a small molecule, namely, cortisol (M.W. = 362 g mol−1), with a concentration of several tens of nanomoles per liter. We demonstrated that the normalized peak wavelength obtained by our measurement system shows good correlation with the cortisol concentration (0 nM, 24.3 nM and 48.6 nM). Our results had a smaller standard deviation than those of the ELISA test.

This paper covers a silicon photonics technology platform that leverages a commercial semiconductor supply chain for the manufacturing of high performance optical transceivers for high performance computing and hyper-scale data-center applications.

In this paper we discuss the different aspects of designing and manufacturing advanced silicon photonics transceivers and focus on utilizing the experience and infrastructure from the CMOS industry. As an example, we discuss the implementation of a 100G CWDM-2 transceiver.

Large progress has been made in the field of silicon photonics since its inception in the late eighties of last century. An intriguing and challenging field of research has evolved with time into a flourishing industry supporting and propelling the growth of data centers and distribute computing known as “the Cloud.”

We assess the reliability of a complete silicon integrated photonics platform through a suite of reliability assurance and qualification tests. We demonstrate high reliability of each component of the silicon photonics optical transceiver.

Field-effect hydrogen gas sensor devices were fabricated with the structure of a series connection between Schottky junctions and β-Ga2O3/6H-SiC heterojunctions. β-Ga2O3 thin films were deposited on n-type and p-type 6H-SiC substrates by gallium evaporation in oxygen plasma. These devices have rectifying properties and were characterized as hydrogen sensors by a Pt electrode. The hydrogen-sensing properties of both devices were measured in the range of 300–500 °C. The Pt/Ga2O3/n-SiC device revealed hydrogen-sensing properties as conventional Schottky diode-type devices. The forward current of the Pt/Ga2O3/p-SiC device was significantly increased under exposure to hydrogen. The behaviors of hydrogen sensing of the devices were explained using band diagrams of the Pt/Ga2O3/SiC structure biased in the forward and reverse directions.

Aiming to develop the compact nuclear magnetic resonance devices, the authors have been developing the uniform magnetic fields in the space between the face-to-face magnetic poles which contain HTS bulk magnets. The authors deformed the original convex shape of the magnetic field distribution to concave by attaching a ferromagnetic iron plate of 20 mm and 100 mm in diameter on one of the pole surfaces. The magnetic field distribution precisely measured along x-axis changed from concave to convex with increasing distance from the magnetic pole surface, which suggested the presence of magnetically flat region. From the results of mapping on the field uniformity data, we have succeeded in obtaining the field uniformity under 500ppm in the space of 4 x 4 x 0.8 mm3 when the magnetic poles emitting concave and convex field distributions were settled face-to-face with various gaps 30-70 mm. This performance exceeded the target value of 1,500ppm which is necessary to detect the NMR signals.

Improved therapeutic outcomes for children with embryonal brain tumors (EBTs) hinge on the development and optimization of novel, targeted therapies able to eradicate tumors without serious treatment-related damage to the central nervous system (CNS). To this end, we describe the design and validation of optimized chimeric antigen receptors (CARs) T-cells that target the EBT-associated antigen Her2. Our studies demonstrate that Her2CAR extracellular spacer domains actively influence T-cell in vitro functional outputs and in vivo responses, with the medium (M-) spacer able to confer the greatest antitumor activity against the most common EBT, medulloblastoma. Furthermore, we show that the juxtamembrane epitope targeted on Her2 precluded short spacer Her2CAR activity; yet, this activity could be rescued when the targeted epitope was expressed in a membrane distal position. Similarly, while modifications that abrogate Fc region interactions in the long spacer Her2CAR rescued in vivo activity, the resultant functional outputs failed to reach the antitumor potency elicited by the M-spacer CAR. Here we also demonstrate the in vitro and in vivo activity of M-spacer CAR T-cells produced by our clinical manufacturing process. Results from this preclinical dataset have directed the implementation of a clinical trial that delivers Her2CAR T-cells locoregionally to patients with EBT tumors, coined BrainChild-01. Collectively, these results reiterate the necessity to tailor CARs to their respective targeted antigen epitope and describe the optimization of Her2-targeted CARs for the treatment of EBT tumors. Citation Format: Adam J. Johnson, Cindy A. Chang, Michael L. Baldwin, Jason K. Yokoyama, Michael C.M. Jensen. Chimeric antigen receptor (CAR) targeted epitope determines optimal CAR spacer length for therapy against medulloblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A032.

Background. Lungischaemia‐reperfusion(I/R)injuryiscorrelatedwithpoorclinicaloutcome. The inflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) are produced by pulmonary epithelial cells during lung transplantation and are considered to be involved in I/R injury. The volatile anaesthetic sevoflurane has been shown to exert a protective effect on I/R injury in various organs. We investigated the effect of sevoflurane on the inflammatory functions of pulmonary epithelial cells in vitro. Methods. Human normal small airway epithelial cells (SAEC) were incubated under anoxic conditions for 24 h with or without sevoflurane and then stimulated with tumour necrosis factor (TNF)-a under hyperoxic conditions for 5 h with or without sevoflurane. After incubation, IL-6, IL-8, and MCP-1 mRNA expression was analysed by quantitative real-time RT‐PCR. The production of IL-6, IL-8, and MCP-1 was assayed by enzyme-linked immunosorbent assay, the effects of sevoflurane on inflammatory gene expression were examined by DNA microarray analysis, and the effects of sevoflurane on NF-kB-mediated inflammatory cytokine production were examined by immunoblotting. Results. Sevoflurane suppressed TNF-a-induced IL-6, IL-8, and MCP-1 gene expression and the production of IL-6 and IL-8 in SAEC under anoxia/reoxygenation conditions. DNA microarray analysis indicated that sevoflurane modulated NF-kB-related gene expression. Sevoflurane significantly inhibited TNF-a-induced translocation of p65 NF-kB into the nucleus. Sevoflurane enhanced TNF-a-induced gene expression of inhibitor k B( IkB) but not of NF-kB. Conclusions.SevofluranesuppressedtheNF-kB-mediatedproductionofpulmonaryepithelial cell-derivedinflammatorycytokines,includingIL-6andIL-8,whicharecapableofcausingI/R injury.

The widespread installation of distributed generation systems is crucial for making optimal use of renewable energy. However, local distribution networks face voltage fluctuation problems if numerous photovoltaic (PV) systems are connected. Recently, energy storage systems that can be installed at commercial customers have been developed. This paper proposes a concept that solves the voltage fluctuation problem in distribution networks with high penetration of PV systems by using customer-side energy storage systems. The distribution network operator (DNO) is allowed to control the output of the energy storage systems of customers during a specific time period in exchange for a subsidy covering a portion of the initial cost of the storage system. The cost effectiveness of the cooperative operation for both customer and DNO is discussed by numerical simulations based on minute-by-minute solar irradiation data. Our results have clarified the possibilities of making voltage management more economical in distribution networks.

Hiroyuki Mitsui1, 2), Mitsumi Arito1), Toshiyuki Sato1), Michiyo K. Yokoyama1), Naoya Suematsu1), Kazuki Okamoto1), Manae S. Kurokawa1), Kazuo Yudo3), Hiroshi Nakamura4), Moroe Beppu2) and Tomohiro Kato1,*) 1)Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan 2)Department of Orthopedic Surgery and 3)Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan 4)Department of Rheumatology, Nippon Medical School, Tokyo, Japan

In this paper we address silicon photonics based optical transceiver technology for applications in advanced data communications such as high performance computing and hyperscale datacenters.

In this paper we discuss design and characterization of silicon-photonics-based 100 Gbps (4×26 Gbps) transceivers for parallel single mode fiber communication. We also address some key underlying technologies including silicon photonics wafer processing, photonic device libraries, light source integration and packaging technologies.

To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13-HOTTIP-IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.

Men have worse survival than premenopausal women after intracerebral hemorrhage (ICH). After ICH, overproduction of iron associated with induction of heme oxygenase-1 (HO-1) in brain was observed. Rodent ICH model using ferrous citrate (FC)-infusion into the striatum to simulate iron overload, showed a higher degree of injury severity in males than in females. However, the participation of HO-1 in sex-differences of iron-induced brain injury remains unknown. The present results showed a higher level of HO-1 expression associated with more severe injury in males compared with females after FC-infusion. Estradiol (E2) contributed to lower levels of FC-induced HO-1 expression in females compared with males. Heterozygote ho-1 KO decreased the levels of FC-induced injury severity, histological lesions, behavioral deficits, autophagy and autophagic cell death in the striatum of males but not in females. Moreover, ho-1 deficiency enhanced the neuroprotection by E2 only in males. These results suggested that over induction of HO-1 plays a harmful role in FC-induced brain injury in a male-specific manner. Suppression of HO-1 combined with E2 exhibits a synergistic effect on neuroprotection against FC-induced striatal injury in males. These findings open up the prospect for male-specific neuroprotection targeting HO-1 suppression for patients suffering from striatal iron overload.

We report on the development of Luxtera's silicon photonics platform for the production of high-speed optical transceivers using a hybrid-integrated approach.

Monitoring biosignals has become more people-friendly since the development of wearable electro-conductive cloth. This paper proposes an application using wearable EMG sensors that estimates the fall risk of elderly people based on co-contraction of the lower limb during walking. Fifty-two healthy elderly people participated in a gait test with continuous EMG of the thigh (rectus femoris and biceps femoris) and cruris (tibialis anterior and gastrocnemius). The participants were categorized into a "faller group" and a "non-faller group" based on their experience of falls in the previous year. Co-contraction of thigh and cruris were determined based on EMG, and were then used to estimate the experience of falling using a linear discrimination method. The results showed that thigh co-contraction during the stance phase can be predictive of falling experience with 65% accuracy.

Fabrication technologies for X-band high gradient accelerating structures have been studied at KEK with SLAC, INFN and CERN. A scanning field emission microscope has been developed at KEK for the observation of the microscopic surface defects which may be related to the rf breakdown trigger. We present the progress on the experimental results of studying field emission characteristics by scanning an arbitrary area of 0.5 mm×0.5 mm on OFHC copper surface using a newly developed scanning field emission microscope.

Personalized immunotherapy has reached a pivotal milestone with the recent approval of CD19-directed chimeric antigen receptor (CAR) T-cell therapies for certain B-cell malignancies. Other than on-target off-tumor autoimmunity, the commonly seen toxicity is severe cytokine release syndrome (sCRS) which is somewhat managed with tocilizumab and corticosteroids. Although the landscape of CAR-T cell development includes >200 clinical trials in various tumor types, success against solid tumors remains a significant challenge. Much of the unmet medical need has been attributed to limited “ideal” tumor-specific targets, tumor heterogeneity, CAR-T cell infiltration/survival, and the presence of an immunosuppressive tumor microenvironment. Due to frequent overexpression in many human cancers, the folate receptor (FR) has become an exploratory target for anti-FRα/β CAR-T cell therapies. We are developing a CAR-T adaptor molecule (CAM)-based therapy that uses the small-molecule bispecific ligand, EC17 (folate-FITC). In this setting, EC17 effectively “paints” FR+ tumors with the FITC antigen to attract anti-FITC CAR-T cells and induce an immune response. As previously confirmed in mice as well as in human clinical studies, EC17 penetrates solid tumors within minutes and is retained due to high affinity for the FR; whereas unbound EC17 rapidly clears from the blood and from receptor-negative tissues. When tested against human xenografts, EC17/CAR-T therapy showed consistent antitumor activity with low or no adverse reactions. However, sCRS was observed under defined experimental conditions. Further testing revealed that sCRS of grade ≥3 (out of a 0-5 scale) can be mitigated or even prevented using intermittent “on-and-off” dosing and/or dose titration of the EC17 CAM. But, under extreme conditions where dose cessation failed, we discovered that intravenous sodium fluorescein (NaFl) could be used as a fast-acting rescue agent to temporarily displace CAR-T cells from their targets and reverse the sCRS symptoms. For translation into first-in-human testing, we selected a high-affinity anti-FITC CAR construct comprising (i) a humanized FITC scFv (E2; 0.75 nM Kd), (ii) an IgG4 hinge-CH2-CH3 spacer fused to a CD28-transmemeber domain, (iii) a second-generation 4-1BB:zeta-endodomain, and (iv) a cell-surface human EGFRt tag. Co-culture experiments were performed using this construct to establish EC17-dependent dose response and confirm target specificity as well as FR expression threshold using a panel of FR-positive cancer cell lines. Clinically relevant EC17 dosing regimens were evaluated using tumor-free and tumor-bearing mice to study CAR-T cell proliferation, cytokine production and the onset/mitigation of sCRS. We confirmed that EC17 administration in the presence of FR+ tumors was the key to drive in vivo CAR-T cell proliferation towards a more persistent phenotype. In addition, higher levels of CAR-T cells were detected in metastatic tumors versus adjacent normal tissues. Finally, EC17/CAR-T cell therapy demonstrated remarkable efficacy against some of the more aggressive and chemo-resistant FR+ tumors of various histology. In summary, our CAM-driven CAR-T cell approach provides antitumor activity with multiple safety control mechanisms. Citation Format: Yingjuan June Lu, Haiyan Chu, Leroy W. Wheeler, Mellissa Nelson, Elaine M. Westrick, Marilynn R. Vetzel, Patrick J. Klein, Adam J. Johnson, Jason K. Yokoyama, Joshua A. Gustafson, Michael C. Jensen, Yong-Gu Lee, Philip S. Low, Christopher P. Leamon. Adaptor controlled CAR-T cell immunotherapy for treatment of folate receptor-alpha/beta positive solid and liquid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-109.

BACKGROUND AND PURPOSE: DLB is recognized as the second major form of dementia in the elderly. The regional pattern of GM atrophy in DLB highly overlaps that in AD. The aim of this study was to identify the critical pattern of atrophy in DLB by using DARTEL, which provides improved registration accuracy compared with that of conventional VBM. MATERIALS AND METHODS: We evaluated 51 patients with probable AD, 43 patients with probable DLB, and 40 age-matched healthy controls. The pattern of GM atrophy in each group was compared by using conventional VBM and VBM-DARTEL. RESULTS: Regional patterns of atrophy identified by using conventional VBM differed significantly from those identified by using VBM-DARTEL. A decrease in GM volume in the MTLs in both AD and DLB was identified with VBM-DARTEL; the decrease was greater in patients with AD than in those with DLB. Comparisons with healthy controls revealed that the WM volume of the whole brain was preserved in patients with DLB. In contrast, a severe bilateral decrease in WM in the MTLs was detected in patients with AD. CONCLUSIONS: VBM-DARTEL provided more accurate results, and it enabled the identification of more localized morphologic alterations than did conventional VBM. Analysis of WM preservation in DLB could help to differentiate this condition from AD.

To study the characteristics of breakdowns in different materials under a high RF field, a high-gradient experiment was proposed with using narrow waveguides having a field of around 140 MV/m at 50 MW power. Two experiments, one on copper (OFC) and another on stainless-steel (AISI-316L), were done. The breakdown rate of the copper waveguide was found to be larger than that of the stainless-steel waveguide at fields higher than several tens of megavolts per meter. The surfaces of both materials were observed after high-field experiments. The area suffering from heavy breakdowns was found to be rugged for the copper waveguide, while that of the stainless-steel smoother than the copper case, even though the heights of dips and bumps were almost the same at 20∼30 microns for the two materials. From these results, it was proven that the breakdown study using narrow waveguide under the high gradient field offered great potential.

We report experimental results from a heavy ion CT system based on the measurement of residual range distribution using an X-ray intensifying screen and a charged coupled device (CCD) camera system. This technique was first investigated by Zygmanski (2000) for proton beams, and they reported that the spatial resolution was significantly degraded by multiple Coulomb scattering (MCS) effects in the irradiated medium. Experiments were done on the spatial resolution phantom by using helium and carbon beams accelerated up to 120 MeV/u and 230 MeV/u by the Heavy Ion Medical Accelerator in Chiba (HIMAC), installed in the National Institute of Radiological Sciences (NIRS) in Japan, using a high performance intensified CCD (ICCD) camera. We show that the MCS blurring effect can be significantly reduced in the reconstructed image by using a carbon beam with this technique. Our results suggest that heavier particles such as carbon would be more useful if this technique is envisioned as a clinical tool to obtain data that would aid proton and/or heavy ion treatment planning.

HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome can result in a fatal intracranial haemorrhage during the perinatal period. We report treatment of a 32-year-old primigravida who fell into a deep coma during labour with fetal distress, complicated by a spontaneous acute subdural haematoma and intracerebral haemorrhage. Simultaneous emergency operations, evacuation of the acute subdural haematoma and a caesarean section, were performed, during which a diagnosis of HELLP syndrome with disseminated intravascular coagulation was made. Both mother and infant recovered, though hemiparesis persisted in the mother. Patients with HELLP syndrome should be managed as high-risk, which requires an excellent working relationship of the physicians involved. Prompt recognition of intracranial haemorrhagic complications and neurosurgical intervention are particularly important.

Background Both fibroblast growth factor-23 (FGF-23) and osteoprotegerin (OPG) are associated with phosphate metabolism, and are produced by bone tissue. Methods In order to clarify the influence of bone turnover on phosphate metabolism, we examined the response of FGF-23 to an oral phosphate load in 4 groups of mice (2 OPG knockout (KO) and 2 wild-type (WT) groups) given either a high-phosphate diet or a normal diet by performing serum and urinary biochemical assays. Results Although there was no significant difference in serum phosphate/ calcium levels between the groups, the decrease in tubular reabsorption rate of phosphate (%TRP) by oral phosphate load was smaller in the OPG KO mice than in the WT mice. FGF-23 level was significantly increased by a high-phosphate diet in WT mice, but not in OPG KO mice. However, there was no significant difference of intact PTH and calcitriol levels between the OPG KO and WT mice. Conclusion Therefore, OPG may play a key role in mediating the response of FGF-23 to an oral phosphate load in bone cells.

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 x 10(7) PFU, plaque-forming unit) plus AxCEAprTK (2 x 10(8) PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 x 10(7) PFU)/GCV or AxCEAprTK (2 x 10(9) PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.

Failures in high-strength steel tendons of prestressed concrete structures are becoming a serious problem, as the deterioration of structures progresses due to aging. The failure is mainly attributed to the corrosion induced in severe environment as salt attack. Intensive studies were made in a laboratory and fields to investigate an applicability of acoustic emission (AE) technique to detect and locate the corrosion-induced failure. Three types of beams post-tensioned by steel bar, strand, and parallel wire cable with three different grout conditions (unbonded, partially grouted and fully grouted) were prepared in the laboratory tests. Failure was introduced by artificial corrosion, charging anodic current to the tendon. It was found that significant AE signals with extremely high amplitudes were produced by failures of steel wires and bars. Linear source location of the events was performed by three AE sensors placed in the center and the two ends of the beams. Reliability was shown to be 82–86% in terms of delectability of the failures. Continuous AE monitoring was carried out in two high-way bridges in service for 24 days. Eighteen AE sensors were placed at strategically selected positions on the post-tensioned beams of these bridges. Artificial AE signals were indirectly detected from the beams due to artificial failures by corrosion in small post-tensioned specimens bonded to the beams. Intensive analysis of the detected AE signals showed that meaningful AE events from the failures are clearly discernable from other sources as traffic noises and hammering. It has been proven that AE is a very useful technique to detect and evaluate failures of high-strength steel tendons in prestressed concrete bridges.